HIV enters a target cell by forming a complex between its own gp160 protein, the cell surface CD4 receptor, and a 7-transmembrane chemokine receptor that serves as a coreceptor for the virus. The binding between gp160 of macrophage (M)-tropic strains of HIV and the (-chemokine receptor CCR5 is complex and relies upon multiple portions of the receptor and various regions of gp160 including the V3 loop. T-tropic HIV uses CXCR4 for entry, while T-tropic SIV uses CCR5. Signaling through the chemokine receptor is not required for HIV entry into a target cell. The purpose of this study is to determine whether gp160, in binding to and using CCR5 as an entry cofactor, signals through CCR5, thus delivering an additional activation signal to the target cell. Signaling was analyzed in two different systems: a flow cytometric analysis of calcium fluxes, and a chemotaxis assay. We have demonstrated that the gp160 protein from M-tropic strains of HIV and SIV can signal through CCR5 and induce a chemotactic response, while gp160 from T-cell tropic HIV strains does not. HIV and SIV may use the ability of their envelope protein to signal through chemokine receptors to increase the activation of target cells, rendering them more susceptible to infection, and cause the accumulation of activated CD4+ T cells in regions of viral replication. Future studies will examine the portions of gp160 and CCR5 required for signaling and will delineate the role of CCR5 signaling in HIV replication.